Day 1 | Day 2
WEDNESDAY, OCTOBER 28
7:30am – 8:30am Registration for Conference B
8:30 Chairperson’s Remarks
Steve Keller, Ph.D., Director, Bioanalytical Sciences, Pre-clinical and Clinical Development, Facet Biotech, Inc.
8:35 FDA Expectations for Immunogenicity Assessment: Is the Target Moving?
Steve Keller, Ph.D., Director, Bioanalytical Sciences, Pre-clinical and Clinical Development, Facet Biotech, Inc.
In contrast to other bioanalytical methodology, immunogenicity assays lack ideal positive controls, suffer from imperfect cutpoints, often rely on specialized reagents making standardization impossible, and ultimately end with a method for identifying neutralizing antibodies that present a myriad of challenges. To provide some consistency, a number of white papers have been published. Using these, you can be armed with the right assays, validated in a manner consistent with industry best practices, and including the right sampling time points. But does the FDA want more? This talk will summarize interaction with the FDA related to immunogenicity for a Ph1 oncology therapeutic antibody.
9:05 Featured Presentation
A Regulatory Perspective on Protein Therapeutics
Susan Kirshner, Associate Chief, Laboratory of Immunology, Office of Biotechnology, FDA
Immunogenicity is a significant safety and efficacy concern for protein therapeutics. This talk will provide a regulatory perspective on the immunogenicity of biological therapeutics including: FDA expectations regarding the submission of assay development and validation data; clinical assessment of immunogenicity; managing immunogenicity and immunogenicity studies as part of comparability exercises. Common pitfalls in submissions will be discussed.
9:35 Sponsored Presentation (Opportunity available, please
contact Ilana Quigley, iquigley@healthtech.com)
9:55 Networking Coffee Break, Poster and Exhibit Viewing
10:30 KEYNOTE
Priorities for EU Guidance on Immunogenicity Risk Assessment for Therapeutic Monoclonal Antibodies
Paul Chamberlain, NDA Advisory Board
New EU guidance is currently in preparation to assist sponsors in developing an appropriate strategy for managing immunogenicity-related risks for monoclonal antibodies. This presentation will consider how the accumulated clinical experience for this of product might be interpreted to identify the priorities for the regulatory approach. This will include selection of bioanalytical methods and presentation of clinical data to regulatory agencies.
11:00 Panel Discussion with the Speakers
11:30 Impact of Formulation and Drug Product Features on Immunogenicity of Proteins
Joël Richard, Ph.D., Senior Director, Head, Drug Product Development, Pharmaceutical Development, IPSEN - Beaufour Ipsen Industrie
The various reasons why a protein-based drug product (DP) can induce immunogenicity will be presented. Excipient-induced and aggregate-induced immunogenicity will be reviewed, and the main features of aggregates inducing immunogenicity will be discussed. The effect of formulation parameters on aggregate-induced immunogenicity will be presented, as well as the most efficient methods to detect and quantify aggregation in a protein formulation. The case of immunogenicity induced by impurities appearing during DP processing (interactions with fill-and-finish equipments), storage and transport will also be addressed. A case study based on a formulation change will emphasize the key role of excipients and protein interactions with containers and closures (leachables and extractables).
12:00pm Focus on Sub-visible Aggregates and their Impact on Immunogenicity
Jack A. Ragheb, M.D., Ph.D., Principal Investigator, Laboratory of Immunology, Division of Therapeutic Proteins, OBP, CDER, FDA. (Tentative.)
It is well established that large protein aggregates are produced during the pharmaceutical manufacturing of therapeutic protein products and that these can enhance immunogenicity. In turn, the patients’ immune response can compromise the efficacy and safety of the therapeutic protein. This talk will focus on 0.2-10 μm subvisible protein aggregates, how they may interact with the immune system, the potential impact these particles may have on a product’s safety and efficacy profile, the factors affecting this risk, and recent efforts to evaluate and control the associated risk.
12:30 End of Immunogenicity Assessment and Clinical Relevance Lunch on Your Own for Conference B Attendees
WEDNESDAY, OCTOBER 28
2:00pm Chairperson’s Opening Remarks
Matthew Baker, Chief Executive Officer and Chief Scientific Officer, Antitope Ltd.
Featured Presentation
2:05 Impact of the Route of Administration on Immunogenicity of a Biotherapeutic: Pre-clinical Case Studies
Boris Gorovits, Ph.D., Director, Drug Safety Metabolism, Bioanalytical R&D, Wyeth
When biopharma sponsors present a case of immunogenicity risk assessment, the route of administration is always listed as a risk factor. This presentation will evaluate the evidence and present non-clinical based case studies where various routes of administration are compared. PK as well as findings will be discussed.
2:35 KEYNOTE
Pre-clinical Studies and Clinical Plans for Tolerance Induction
Richard Garman, Ph.D., Scientific Director, Immunology Research & Development, Genzyme Corp.
Antibody responses that develop against protein therapeutics can impact patient safety and therapeutic efficacy. In an effort to control therapy-specific antibody responses, several approved immunosuppressive agents, including mycophenolate mofetil, cyclosporine A with azathioprine, CTLA4-Ig, rapamycin, cyclophosphamide and methotrexate, were evaluated for the ability to induce immune tolerance to protein therapeutics in mice. Of these, only methotrexate induced a long-lived reduction in antibody responses. Three weekly courses of low-dose methotrexate suppressed antibody responses through at least eight months of weekly therapeutic protein treatment. Currently, low-dose methotrexate is under clinical evaluation as part of an immune tolerance induction regimen.
3:05 Benefits of Fusion of PEG-like Protein Sequences to Reduce Immunogenicity
Volker Schellenberger, Ph.D., Vice President, Drug Discovery, Amunix, Inc.
PEG-like protein sequences that mimic the biophysical properties of PEG can be directly fused to most drug proteins, allowing efficient recombinant production and eliminating the need for chemical PEG conjugation. Conjugated PEG-like sequences to multiple approved biopharmaceuticals result in high in vivo potency comparable to PEGylated proteins as well as long half-lives that enable multi-week dosing intervals. Fusion proteins to PEG-like sequences show no or extremely low immunogenicity in multiple in vivo studies. Recombinant PEG-like sequences are stable in blood but are rapidly degraded by intracellular proteases. This offers an important safety advantage over chemical PEG that is not biodegradable and has resulted in kidney vacuolization.
3:35 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 Detection of Protein Structures Responsible for Immunogenicity to Provide Safer, Less Immunogenic Biopharmaceuticals
Barend Bouma, Ph.D., Chief Operating Officer & Head, Research & Development, Crossbeta Biosciences BV
This presentation will report on the immune response and breaking of tolerance against interferon-alpha with conformational changes, accompanied by adoption of amyloid-like crossbeta structure and misfolding. For several biologics the level of crossbeta structure increases upon prescribed storage, and results indicate that misfolding of therapeutic proteins is a risk factor for immunogenicity. Methods for detecting potentially harmful misfolded protein entities with crossbeta structures will be described together with affinity matrices under development to remove harmful entities with crossbeta structures from biopharmaceutical preparations.
4.30 Sponsored Presentation (Opportunity available, please contact Ilana Quigley, iquigley@healthtech.com)
5:00 Break Out Sessions
Break out sessions are interactive moderated discussions on topics of interest to investigators in the field of immunogenicity. Problems are discussed and solutions are shared.
Table 1
How Serious are Antibodies to Protein and Antibody Therapeutics for the Industry?
Moderator: Fiona A. Harding, Ph.D., Associate Director, New Technologies, Facet Biotech, Inc.
Table 2
How Predictive are the Methods to Analyse T cell Epitopes?
Moderator: Matthew Baker, Ph.D., Chief Scientific Officer, Antitope Ltd.
Pros and cons of in silico, in vitro and in vivo methods. Is the presence of T cell epitopes indicative of immunogenicity in the clinic? Will the FDA require prediction of T cell epitopes in the future?
Table 3
The Risk Assessment Process Based on Examples of Mock Protein-based Drug Molecules
Moderator: Boris Gorovits, Ph.D., Director, Bioanalytical R&D, Wyeth
What is immunogenicity risk? Product properties, patient characteristics and other important issues to consider What we can and cannot control Bioanalytical strategy Discussion will be based on examples of mock protein drug molecules
Table 4
The Impact of the Dosing Regimen on Drug Immunogenicity
Moderator: Volker Schellenberger, Ph.D., Vice President, Drug Discovery, Amunix, Inc.
Do drug holidays result in increased immunogenicity risk? Are low drug doses more or less immunogenic? Can long half-life and continuous drug exposure reduce the immunogenicity risk? How effective is PEGylation in reducing immunogenicity?
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6:00 Networking Cocktail Reception in the Exhibit Hall (Opportunity available, please contact Ilana Quigley, iquigley@healthtech.com)
7:00 End of Day One of Immunogenicity Prediction and Reduction
For more information, please contact:
Nicole Lyscom, Ph.D.
Conference Producer
Cambridge Healthtech Institute (CHI)
Phone: +44-1483-826359
E-mail: nlyscom@healthtech.com
For sponsorship information, please contact:
Ilana Quigley
Manager, Business Development
Cambridge Healthtech Institute (CHI)
Phone: +1-781-978-5457
Cell: +1-857-636-2334
Email: iquigley@healthtech.com